1. Field of the Invention
1-Amino-alkylcyclohexane compounds which are systemically-active as NMDA receptor antagonists, pharmaceutical compositions comprising the same, method of preparation thereof, and method of treating CNS disorders which involve disturbances of glutamatergic transmission therewith.
2. Prior Art
Antagonism of glutamate receptors of the N-methyl-D-aspartate (NMDA) type has a potentially wide range of therapeutic applications [19]. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site, strychnine-insensitiveglycine site (glycine.sub.B), polyamine site, and phencyclidine site located inside the cation channel. The NMDA receptor channel blockers act in an uncompetitive "use-dependent" manner, meaning that they usually only block the channel in the open state. This use-dependence has been interpreted by many to mean that stronger activation of the receptor should lead to a greater degree of antagonism. Such a mode of action has further been taken to imply that this class of antagonist may be particularly useful when overactivation of NMDA receptors can be expected, such as in epilepsy, ischaemia, and trauma. However, initial clinical experience with the selective, high affinity, strongly use-dependent uncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801) has been disappointing. Namely, therapeutic efficacy in epilepsy was poor while some psychotropic side effects were apparent at therapeutic doses. These observations, together with the fact that phencyclidine abusers experience similar psychotropic symptoms, has led to the conclusion that uncompetitive antagonism of NMDA receptors may not be a promising therapeutic approach.
However, the use of more elaborate electrophysiological methods indicates that there is no equality between different uncompetitive antagonists since factors such as the speed of receptor blockade (on-off kinetics) and the voltage-dependence of this effect may determine the pharmacodynamic features in vivo, i.e., therapeutic safety as well. Paradoxically, agents with low to moderate, rather than high, affinity may be desirable. Such findings triggered a reconsideration of the concept of uncompetitive antagonism of NMDA receptors in drug development [19, 22]. At present, many such agents are at different stages of development, e.g., carvedilol, ADCI, ES 242S, remacemide, felbamate, and budipine. On the other hand, uncompetitive NMDA receptor antagonists, such as amantadine and memantine--which fulfill the above criteria--have been used clinically for several years in the treatment of Parkinson's disease and dementia respectively, and do indeed rarely produce side effects at the therapeutic doses used in their respective indications.
In view of the above mentioned evidence, we have developed a series of novel uncompetitive NMDA receptor antagonists based on the 1-aminoalkylcyclohexane structure. The present study was devoted to compare the NMDA receptor antagonistic properties of these 1-aminoalkylcyclohexane derivatives in receptor-binding assays, patch clamp experiments, excitotoxicity in vitro, three convulsion models, and two models of motor impairment. The substitutions of these 1-aminoalkylcyclohexanes are detailed in Table 6.